Alpha Ketoglutarate: Help for Brain, Gut, Bone, Muscle, and Anti-Aging Too

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In this article, we will explore Alpha-Ketoglutarate supplements, including their uses, recommended dosage, and effects on health and performance. Whether you’re an athlete aiming to improve muscle recovery or someone interested in enhancing overall health, understanding Alpha-Ketoglutarate supplements is important. Join us as we examine the science behind Alpha-Ketoglutarate and its impact on health and performance. Learn how Alpha-Ketoglutarate supplements may support your journey toward better health and vitality.

What is Alpha Ketoglutarate?

Alpha-ketoglutarate (α-KG or AKG) is a crucial molecule made within the body. It is an intermediate molecule in the citric acid cycle (aka the Krebs Cycle or TCA cycle) that turns food and oxygen into energy. Researchers believe that it’s the rate-limiting molecule in the citric acid cycle, and therefore energy production, of the organism.

Besides its role in the citric acid cycle, alpha-ketoglutarate helps create the amino acids glutamine and glutamate (building blocks for proteins). It is also involved in other cell processes, such as controlling certain enzymes and responding to low oxygen levels.

Alpha-ketoglutarate (AKG) is a compound that plays a crucial role in several metabolic processes in the body. While it is not typically used as a dietary supplement in the same way as vitamins or minerals, some potential health benefits have been associated with AKG:

What Are the Health Benefits of Alpha-Ketoglutarate?

• Energy Production: Alpha-ketoglutarate (AKG) is integral to the citric acid cycle, a key process in cellular energy production. This cycle, which relies on AKG, is crucial for generating adenosine triphosphate (ATP), the body’s main energy source, supporting various metabolic functions and possibly extending lifespan while delaying age-related diseases. [PMC4703346]
• Muscle Recovery: AKG supplements are used by athletes and bodybuilders to aid muscle recovery and reduce exercise-induced muscle damage. Research shows that AKG may prevent muscle breakdown and improve muscle function, offering potential benefits for treating muscle wasting conditions. [PMC6266637]
• Antioxidant Activity: AKG has antioxidant properties, which means it can help neutralize harmful free radicals in the body, potentially reducing oxidative stress and cellular damage. AKG helps protect against damage by boosting antioxidants and breaking down harmful molecules, offering promise for treating diseases. PMC5884300
• Brain Health: There is emerging research indicating that alpha-ketoglutarate (AKG) could potentially support brain health and cognitive function by helping maintain cellular energy balance, possibly through its interaction with the mTOR pathway. However, further studies are required to fully understand its neuroprotective effects. PMC10074856
• Immune Support: Researchers found that alpha-ketoglutarate (αKG) can modify the function of dendritic cells (DCs), reducing their tendency to cause inflammation and enhancing their ability to produce anti-inflammatory cells. This suggests that αKG might contribute to a balanced immune response and could be explored for developing improved treatments for immune-related diseases. PMC10845299
• Wound Healing: In some clinical settings, alpha-ketoglutarate (AKG) has been incorporated into wound healing formulations and used as part of nutritional support for patients recovering from surgery or trauma. The development of polyesters of alpha-ketoglutarate (paKG) materials, which release alpha-ketoglutarate (aKG) slowly and enhance wound healing in experimental models, suggests a possibility for AKG-based therapies in tissue regeneration. PMC10517069
• Amino Acid Metabolism: AKG is a key player in cell metabolism because it helps produce glutamine and glutamate. These compounds are essential for building proteins, preventing muscle breakdown, and providing energy for cells in the gut. This highlights its role in amino acid metabolism and its implications for protein synthesis and overall muscle health. PMC4703346
• Heart Health: Alpha-ketoglutarate (AKG) is a natural compound that shows promise in improving heart function by reducing oxidative damage and promoting the removal of damaged cell components, suggesting it could be a potential treatment for heart failure. PMC8353361
• Anti-Aging: Some research shows that α-KG might help slow down the aging process by improving cell health and reducing damage to cells. One study in mice found that α-KG extended their lifespan. [PMC8508957] In flies, researchers found evidence that AKG may turn off mTOR and turn on AMPK. [PMC6629006]

• Kidney health: α-KG has been studied in people with kidney problems, but more research is needed before it can be considered safe or effective for people with kidney disease. People with kidney disease must not take nutritional supplements without discussing them with their physician. Nevertheless, one study showed that taking α-KG helped lower levels of harmful substances in the blood of patients with chronic kidney disease [PMC5419544].

Promotes Brown Fat-The Kind That Burns Calories

Feel free to skip the technicalities if you wish, but researchers have been making some fascinating discoveries.

Brown adipose tissue (BAT) is different from white adipose tissue in both function and structure. While white adipose stores energy as fat, brown adipose specializes in burning energy to generate heat, a process vital for maintaining body temperature in cold conditions. This ability is due to a high concentration of mitochondria within brown fat cells, which contain a special protein called uncoupling protein-1 (UCP1). UCP1 allows these mitochondria to convert energy directly into heat instead of storing it as ATP, the cell’s usual energy currency. This phenomenon, known as non-shivering thermogenesis, is especially crucial in newborns and hibernating animals. For adults, stimulating brown fat can be beneficial for managing weight and enhancing metabolic health, as it helps burn off excess calories as heat.

UCP1 in brown fat mitochondria doesn’t directly convert fat into heat. Instead, it disrupts the normal process of ATP synthesis by causing protons to leak across the mitochondrial membrane. This disruption leads to a less efficient production of ATP, causing the energy, which would normally be used in ATP synthesis, to be released as heat.

Since the identification of abundant metabolically active BAT in adult humans in 2009 [6], the central role of brown and beige fat in obesity and metabolic dysfunction prevention has been rapidly recognized. BAT mass is negatively correlated with obesity in humans. 

Alpha-ketoglutarate for adipose tissue rejuvenation [PMC7425480]

As we age, our bodies struggle to form new white fat cells, leading to metabolic issues due to enlarged existing cells. One study found that middle-aged mice have lower levels of alpha-ketoglutarate (AKG), essential for creating brown fat cells. By supplementing AKG, researchers saw improvements in these mice, including reduced weight gain and better glucose tolerance on a high-fat diet. AKG also promoted the activity of genes and proteins associated with brown fat and improved the functionality of these fat cells. Thus, AKG supplementation in middle-aged mice supports healthier fat metabolism and protects against obesity. Since humans have similar metabolic systems to mice in many ways, researchers hope this will translate to human health. [PMC6974731]

Measuring Aging

DNA methylation is a natural process where certain chemicals, called methyl groups, attach to our DNA. As we age, these methylation patterns change. The TruAge methylation clock is a scientific tool that estimates biological age based on DNA methylation patterns. The TruAge clock analyzes these patterns in the DNA through a simple blood or saliva sample. By comparing your methylation pattern to thousands of others from people of known ages, the TruAge clock can estimate your biological age, which might differ from your chronological age based on your health and lifestyle.

This epigenetic test (TruAge) method of measuring age was used by researchers to test the anti-aging effects of Alpha Ketoglutarate supplements. Fourty-two participants with an average age of 63 took 1000 mg calcium-AKG for 4 to 10 months (7 months on average). The men’s formula also contained 900 mg Vitamin A while the women’s formula contained an additional 1000 IU Vitamin D. TruAge measures the methylation of 9 areas of 3 genes to estimate biological age. The participants had an average 7.96 year younger biologic age score at the end than at baseline (8.44 years for men and 6.98 years for women).

The researchers note that they may not be using a valid test for biological aging. Here’s why: AKG may demethylate DNA sites used by the TruAge test to estimate biological age. So this research may possibly be showing a larger effect on methylation-based aging clocks than it would on other indicators of biologic age.

Other reasons to be cautious about these results include researchers commercial affiliations. One of the investigators is a consultant and board member for the company that sells the supplement used in this study. Two investigators are affiliated with the company that markets the TruAge test used in the study. [PMCID: PMC8660611]

Alpha Ketoglutarate and Anti-Aging Gene Experiments

In a Youtube Video, Dr. Sinclair, a respected researcher in the field of aging, briefly explains that Alpha Ketoglutarate affects the OSK genes (OCT4, SOX2, KLF4). He explains that these are 3 genes that are usually switched on only in embryos and they play a part in keeping stem cells young. He explains that these 3 genes can be activated by Alpha Ketoglutarate. For those who are interested in the extremely technical details of this process, they are further discussed in this 2019 article. [PMC6462505, PMC4703346]

Is Alpha Ketoglutarate Safe?

Alpha-ketoglutarate supplements are safe when taken as directed. Numerous studies and clinical trials have demonstrated their safety profile, with few reported adverse effects. Alpha-ketoglutarate is a naturally occurring molecule in the body and plays a vital role in the citric acid cycle, a fundamental metabolic process. When used as a dietary supplement, it is typically well-tolerated and does not pose significant health risks for most individuals.

Medication Interactions with Alpha Ketoglutarate.

• Anticoagulant Medications: Alpha-ketoglutarate may interact with anticoagulant medications, increasing the risk of bleeding. It is important to monitor blood clotting parameters and consult with a healthcare professional to ensure safe use.
• Potassium-Sparing Diuretics: Alpha-ketoglutarate supplements, particularly those containing potassium, may interact with potassium-sparing diuretics, leading to high potassium levels in the body. Regular monitoring and dosage adjustments may be necessary.
• Calcium Channel Blockers: Alpha-ketoglutarate may interact with calcium channel blockers, potentially affecting their effectiveness or absorption. Close monitoring and dosage adjustments may be required under healthcare professional guidance.
• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): Alpha-ketoglutarate may interact with NSAIDs, which can impact the therapeutic effects of these medications. Follow healthcare professional advice on appropriate dosages and potential adjustments.
• Potassium Supplements: Alpha-ketoglutarate supplements containing potassium may interact with other potassium supplements, potentially leading to high potassium levels. Monitor potassium levels and adjust dosages as recommended.

Supplements Interactions with Alpha Ketoglutarate

• Creatine: Alpha-ketoglutarate may interact with creatine, a popular supplement used for athletic performance and muscle gain. This interaction can potentially enhance the effects of creatine.
• Branched-Chain Amino Acids (BCAAs): Alpha-ketoglutarate may interact with BCAA supplements, which are commonly used for muscle recovery and athletic performance. This interaction can potentially enhance the effects of BCAAs. Monitor your response.
• Nitric Oxide Boosters: Alpha-ketoglutarate is often included in nitric oxide boosting supplements, which are used for enhancing blood flow and exercise performance. This combination can potentially amplify the effects of nitric oxide boosters. Monitor your response.
• Pre-Workout Supplements: Alpha-ketoglutarate is sometimes included in pre-workout supplements, which are used to enhance energy, focus, and exercise performance. This combination can potentially enhance the effects of pre-workout supplements.
• Other Energy or Performance Supplements: Alpha-ketoglutarate may be found in various energy or performance-enhancing supplements. It is advisable to read product labels.

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To Sum It Up

Alpha Ketoglutarate supplements offer a promising avenue for people who want to enhance their health and performance. Throughout this article, we have explored the benefits of Alpha Ketoglutarate supplements. From supporting muscle recovery to optimizing overall well-being, these supplements have shown potential in various areas. By understanding the potential benefits and limitations of Alpha Ketoglutarate supplements, you can make informed decisions on how they may fit into your health and fitness goals.

This Article is Not a Substitute for Medical Advice

Dietary supplements are not designed to diagnose, treat, cure, or prevent any disease. The Supplement Sciences website seeks to provide comprehensive access to the most relevant supplement information along with convenient online ordering. We do not provide medical advice and cannot guarantee that every product suggested is completely without risk. Since each person is unique in their health history and medication use, it is important to discuss supplements with your personal physician. Specifically, pregnant women and individuals being treated for cancer or liver or kidney problems must consult their physician about every nutritional supplement they plan to take. People taking medications for the treatment of HIV or with a history of organ transplant must not take supplements without consulting with their physician.

More Technical Detail

Alpha Ketoglutarate is part of KGDHC pictured below–It’s the rate-limiting step in the Krebs/TCA cycle. But did you know that this classic energy cycle can run in reverse?

The “reductive pathway” can be thought of as a reverse or backward version of the TCA (tricarboxylic acid) cycle’s normal metabolism. In the context of the TCA cycle, there are two main phases: the oxidative phase, which generates energy through the oxidation of acetyl-CoA, and the reductive phase, which involves reactions where intermediates of the cycle can be used for biosynthetic purposes.

When people refer to the “reductive pathway,” they are often referring to a reversal of the TCA cycle’s oxidative phase. This can occur under specific conditions where certain intermediates of the TCA cycle are used in biosynthetic reactions to produce molecules such as amino acids and fatty acids. These biosynthetic reactions can effectively reverse some of the oxidative reactions of the TCA cycle.

One notable example is the conversion of oxaloacetate (an intermediate of the TCA cycle) to malate or pyruvate, which can then be used for biosynthesis. This reversal of TCA cycle reactions allows cells to use TCA cycle intermediates to produce the building blocks required for cell growth and proliferation.

So, in a sense, the reductive pathway can be seen as the TCA cycle running backward from its typical energy-producing metabolism to support the synthesis of essential molecules for cell growth and function.